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1.  Dichlorido[N-(2-pyridylmethyl­idene)benzene-1,4-diamine]zinc(II) 
In the title compound, [ZnCl2(C12H11N3)], the ZnII atom is four-coordinated by two N atoms from an N-(2-pyridylmethyl­ene)benzene-1,4-diamine ligand and two Cl atoms in a distorted tetra­hedral geometry. In the crystal, the complex mol­ecules are connected by N—H⋯Cl and C—H⋯Cl hydrogen bonds into a two-dimensional layer structure parallel to (110).
doi:10.1107/S1600536810015138
PMCID: PMC2979197  PMID: 21579066
2.  The effects of dietary restriction on oxidative stress in rodents 
Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends lifespan in multiple species. However, it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules. The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. Here we present a comprehensive review of the existing literature on the effect of DR on mitochondrial ROS generation, antioxidant enzymes and oxidative damage. In a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging.
doi:10.1016/j.freeradbiomed.2013.05.037
PMCID: PMC4017324  PMID: 23743291
Dietary restriction; calorie restriction; oxidative stress; reactive oxygen species; antioxidant enzymes; oxidative damage; aging
3.  The Emerging Nexus of Active DNA Demethylation and Mitochondrial Oxidative Metabolism in Post-Mitotic Neurons 
The variable patterns of DNA methylation in mammals have been linked to a number of physiological processes, including normal embryonic development and disease pathogenesis. Active removal of DNA methylation, which potentially regulates neuronal gene expression both globally and gene specifically, has been recently implicated in neuronal plasticity, learning and memory processes. Model pathways of active DNA demethylation involve ten-eleven translocation (TET) methylcytosine dioxygenases that are dependent on oxidative metabolites. In addition, reactive oxygen species (ROS) and oxidizing agents generate oxidative modifications of DNA bases that can be removed by base excision repair proteins. These potentially link the two processes of active DNA demethylation and mitochondrial oxidative metabolism in post-mitotic neurons. We review the current biochemical understanding of the DNA demethylation process and discuss its potential interaction with oxidative metabolism. We then summarise the emerging roles of both processes and their interaction in neural plasticity and memory formation and the pathophysiology of neurodegeneration. Finally, possible therapeutic approaches for neurodegenerative diseases are proposed, including reprogramming therapy by global DNA demethylation and mitohormesis therapy for locus-specific DNA demethylation in post-mitotic neurons.
doi:10.3390/ijms151222604
PMCID: PMC4284726  PMID: 25490140
active DNA demethylation; mitochondrial oxidative metabolism; TET (ten-eleven translocation) methylcytosine dioxygenases; post-mitotic neurons; neurodegeneration
4.  Contract Research Organizations (CROs) in China: integrating Chinese research and development capabilities for global drug innovation 
Globalization and Health  2014;10(1):78.
The significance of R&D capabilities of China has become increasingly important as an emerging force in the context of globalization of pharmaceutical research and development (R&D). While China has prospered in its R&D capability in the past decade, how to integrate the rising pharmaceutical R&D capability of China into the global development chain for innovative drugs remains challenging. For many multinational corporations and research organizations overseas, their attempt to integrate China’s pharmaceutical R&D capabilities into their own is always hindered by policy constraints and reluctance of local universities and pharmaceutical firms. In light of the situation, contract research organizations (CROs) in China have made great innovation in value proposition, value chain and value networking to be at a unique position to facilitate global and local R&D integration. Chinese CROs are now being considered as the essentially important and highly versatile integrator of local R&D capability for global drug discovery and innovation.
doi:10.1186/s12992-014-0078-4
PMCID: PMC4240890  PMID: 25406839
Contract research organization; CRO; Pharmaceutical R&D; Global integration; China
5.  MiR-146a rs2910164 polymorphism increases risk of gastric cancer: A meta-analysis 
World Journal of Gastroenterology : WJG  2014;20(41):15440-15447.
AIM: To systematically evaluate the association between the miR-146a rs2910164 polymorphism and susceptibility to gastric cancer.
METHODS: A comprehensive electronic search was conducted for articles published up until January 27, 2014 in Medline (PubMed), Excerpta Medica Database (Embase), the Cochrane Library and Google Scholar. Only case-control studies published in English that evaluated the association between the miR-146a rs2910164 polymorphism and susceptibility to gastric cancer were included. Furthermore, only studies with sufficient data allowing for calculation of odds ratio (OR) and corresponding 95% confidence interval (CI) were included. These values were used in the quantitative synthesis to assess the strength of the association between the miR-146a rs2910164 polymorphism and risk of gastric cancer.
RESULTS: The database search identified 1002 eligible studies, of which seven (comprising 4112 cases and 5811 controls) were included for the meta-analysis. The results indicate that miR-146a rs2910164 polymorphism is more likely to be associated with gastric cancer risk. In the overall analysis, a significantly increased cancer risk was found in the heterozygote (GG vs GC) comparison (OR = 1.14, 95%CI: 1.03-1.27; P = 0.01 for pooled OR). In the ethnicity subgroup analysis, a similar result was found among Caucasians (OR = 1.36, 95%CI: 1.01-1.85; P = 0.04 for pooled OR). In the stratified analysis by quality of studies, a significantly increased cancer risk was found in the heterozygote comparison among high quality studies (OR = 1.12, 95%CI: 1.01-1.26; P = 0.04 for pooled OR). When stratified on the basis of sample size, a significantly increased cancer risk was found among small sample size subgroups for the allelic (G vs C: OR = 1.16, 95%CI: 1.03-1.30; P = 0.01), homozygote (GG vs CC: OR = 1.33, 95%CI: 1.03-1.73; P = 0.03) and recessive model (GG vs GC + CC: OR = 0.05, 95%CI: 0.00-0.10; P = 0.03) comparisons.
CONCLUSION: The miR-146a rs2910164 polymorphism is associated with increased gastric cancer risk, particularly evident in high quality studies with small sample sized Caucasian populations.
doi:10.3748/wjg.v20.i41.15440
PMCID: PMC4223278  PMID: 25386093
Gastric cancer; MiR-146a; Polymorphism; Risk; Meta-analysis
6.  MicroRNA-145: a potent tumour suppressor that regulates multiple cellular pathways 
MicroRNAs are endogenous, small (18–25 nucleotides) non-coding RNAs, which regulate genes expression by directly binding to the 3′-untranslated regions of the target messenger RNAs. Emerging evidence shows that alteration of microRNAs is involved in cancer development. MicroRNA-145 is commonly down-regulated in many types of cancer, regulating various cellular processes, such as the cell cycle, proliferation, apoptosis and invasion, by targeting multiple oncogenes. This review aims to summarize the recent published literature on the role of microRNA-145 in regulating tumourigenesis and progression, and explore its potential for cancer diagnosis, prognosis and treatment.
doi:10.1111/jcmm.12358
PMCID: PMC4244007  PMID: 25124875
microRNA-145; proliferation; invasion; differentiation; angiogenesis
7.  Unliganded Thyroid Hormone Receptor Regulates Metamorphic Timing via the Recruitment of Histone Deacetylase Complexes 
Anuran metamorphosis involves a complex series of tissue transformations that change an aquatic tadpole to a terrestrial frog and resembles the postembryonic perinatal period in mammals. Thyroid hormone (TH) plays a causative role in amphibian metamorphosis and its effect is mediated by TH receptors (TRs). Molecular analyses during Xenopus development have shown that unliganded TR recruits histone deacetylase (HDAC)-containing N-CoR/SMRT complexes and causes histone deacetylation at target genes while liganded TR leads to increased histone acetylations and altered histone methylations at target genes. Transgenic studies involving mutant TR-cofactors have shown that corepressor recruitment by unliganded TR is required to ensure proper timing of the onset of metamorphosis while coactivator levels influence the rate of metamorphic progression. In addition, a number of factors that can influence cellular free TH levels appear to contribute the timing of metamorphic transformations of different organs by regulating the levels of unliganded vs. liganded TR in an organ-specific manner. Thus, the recruitment of HDAC-containing corepressor complexes by unliganded TR likely controls both the timing of the initiation of metamorphosis and the temporal regulation of organ-specific transformations. Similar mechanisms likely mediate TR function in mammals as the maturation of many organs during postembryonic development is dependent upon TH and resembles organ metamorphosis in amphibians.
doi:10.1016/B978-0-12-396968-2.00010-5
PMCID: PMC4180093  PMID: 23962846
8.  Downregulation of miR-193a-5p correlates with lymph node metastasis and poor prognosis in colorectal cancer 
World Journal of Gastroenterology : WJG  2014;20(34):12241-12248.
AIM: To investigate the correlation of miR-193a-5p with lymph node metastasis and postoperative survival of colorectal cancer (CRC) patients.
METHODS: A total of 304 formalin-fixed, paraffin-embedded specimens (69 paired cancer and normal tissues, 55 primary tumors of stage III CRC and matched lymph nodes, and 56 primary tumors of stage II CRC) were included in this study. The relative expression levels of miR-193a-5p in the normal mucosa, primary cancer, and metastatic lymph node lesions were measured by quantitative real-time reverse transcriptase polymerase chain reaction. We evaluated the association of its expression with colorectal cancer lymph node metastasis, clinicopathological factors, and patient survival.
RESULTS: The relative expression level of miR-193a-5p was significantly lower in CRC tissues than in the normal mucosa (P = 0.0060). The expression levels of miR-193a-5p were lower in primary CRC tissues with lymph node metastases than in those without metastases (P = 0.0006), and decreased expression of miR-193a-5p correlated with advanced lymph node metastatic stage (P = 0.0007). Kaplan-Meier analysis showed that patients with low miR-193a-5p expression had decreased disease-free survival (DFS) (P = 0.0026) and poor overall survival (OS) (P = 0.0003). Interestingly, for the group of patients with lymph node metastases, miR-193a-5p expression was also related to survival. Patients with low miR-193a-5p expression had decreased DFS (P = 0.0262) and poor OS (P = 0.0230). Moreover, multivariate analysis indicated that downregulation of miR-193a-5p was an independent predictor of poor OS.
CONCLUSION: Downregulation of miR-193a-5p correlates with lymph node metastasis and poor survival of CRC. miR-193a-5p may be a useful biomarker for CRC diagnosis, metastasis and prognosis prediction.
doi:10.3748/wjg.v20.i34.12241
PMCID: PMC4161809  PMID: 25232258
miR-193a-5p; Colorectal cancer; Lymph node metastasis; Prognosis; Biomarker
9.  Acute exposure of methylglyoxal leads to activation of KATP channels expressed in HEK293 cells 
Acta pharmacologica Sinica  2013;35(1):58-64.
Diabetes is characterized by hyperglycemia and excessive production of metabolites. One of these metabolites is the highly reactive carbonyl, methylglyoxal (MGO). MGO can readily react with biomolecules leading to cellular dysfunction. Here we showed that acute MGO application led to a dose-dependent activation of KATP channels, a major vascular tone regulator and a critical pharmacological target for treating diabetes. Both Kir6.1 and Kir6.2 containing KATP channels were targeted by MGO in a SUR subunit independent manner. Single channel analysis showed that MGO mediated KATP channel activation via enhancement of channel open probability, leaving the channel conductance unaltered. This modulation appeared to be due to the direct interaction of MGO with the KATP channel, without the need for additional cell signaling pathways. Moreover, MGO mediated KATP channel activity was completely reversed with bath solution washout. Taken together, these data suggest that acute exposure to MGO activates KATP channels through direct, non-covalent and reversible interactions with the Kir6.x subunit, suggest a potential target for pharmacological intervention towards vascular complications of diabetes.
doi:10.1038/aps.2013.122
PMCID: PMC4075750  PMID: 24122011
potassium channel; ATP-sensitive potassium channel; diabetes; reactive carbonyl species; RCS; diabetic vascular complications
10.  Tumor Cell Targeting Using Folate-Conjugated Fluorescent Quantum Dots and Receptor-Mediated Endocytosis 
Clinical chemistry  2009;55(5):955-963.
BACKGROUND
Luminescent nanobioprobes with cell-targeting specificity are likely to find important applications in bioanalysis, biomedicine, and clinical diagnosis. Quantum dots (QDs) are unique and promising materials for such a purpose because of their fluorescence and large surface area for attaching cell-targeting molecules.
METHODS
We produced water-dispersible QDs by coating hydrophobic QDs with small amphiphilic polyethylene glycol (PEG) molecules via hydrophobic interactions. We covalently coupled folate (FA) onto the water-dispersible PEG-coated QDs (PEG-QDs) to produce FA-coupled PEG-QDs (FA-PEG-QDs).
RESULTS
These FA-PEG-QD nanoparticles functioned as fluorescent nanobioprobes that specifically recognized folate receptors (FRs) overexpressed in human nasopharyngeal cells (KB cells) but not in an FR-deficient lung carcinoma cell line (A549 cells). Using confocal fluorescence microscopy, we demonstrated uptake of FA-PEG-QDs by KB cells but no uptake of folate-free PEG-QDs. The specificity of this receptor-mediated internalization was confirmed by comparing the uptake by KB vs A549 cells.
CONCLUSIONS
Our results suggest that such cell-targeting fluorescent nanobioprobes are potentially very powerful tools for recognizing target cells and delivering and tracking drugs and other therapeutic materials.
doi:10.1373/clinchem.2008.113423
PMCID: PMC4151316  PMID: 19282359
11.  The role of Aurora A in hypoxia-inducible factor 1α-promoting malignant phenotypes of hepatocelluar carcinoma 
Cell Cycle  2013;12(17):2849-2866.
Overexpression of both hypoxia-inducible factor 1α (HIF-1α) and Aurora A has been found in hepatocelluar carcinoma (HCC). However, whether HIF-1α and Aurora A synergistically promote malignant phenotypes of HCC cells is unknown. The purpose of this study was to investigate the roles and functional correlation of HIF-1α and Aurora A in HCC progression. Immunohistochemistry was performed to detect HIF-1α and Aurora A protein expression in 55 primary HCC and corresponding non-tumor tissues and their clinical significance. Gene knockout technology using short hairpin RNA (shRNA) was used to knockdown expression of HIF-1α or Aurora A and analyze their effects on malignant phenotypes of HCC cells. The transcriptional regulation of Aurora A by HIF-1α and the possible downstream molecular signaling pathways were also determined. Results showed that hypoxia could induce the increased expression of HIF-1α and Aurora A in HCC cells. Also, shRNA-mediated HIF-1α downregulation could lead to the decreased Aurora A expression and inhibition of growth or invasion in HCC cells. Moreover, HIF-1α could transcriptionally regulate Aurora A expression by binding to hypoxia-responsive elements in the Aurora A promoter and recruiting the coactivator-p300/CBP. Additionally, shRNA-mediated Aurora A knockdown could mimic the effects of HIF-1α downregulation on phenotypes of HCC cells, and overexpression of Aurora A could partially rescue the phenotypical changes of HCC cells induced by HIF-1α downregulation. Further research indicated that activation of Akt and p38-MAPK signaling pathways mediated the downstream effects of HIF-1α and Aurora A in HCC cells under hypoxic condition. Taken together, our findings indicated that Aurora A might be a key regulator of HIF-1α-promoting malignant phenotypes of HCC by activation of Akt and p38-MAPK signaling pathways.
doi:10.4161/cc.25916
PMCID: PMC3899198  PMID: 23966163
Aurora A; hepatocelluar carcinoma; hypoxia-inducible factor 1α; malignant phenotype; promoter
12.  A short motif in Kir6.1 consisting of 4 phosphorylation repeats underlies the vascular KATP channel inhibition by protein kinase C 
The Journal of biological chemistry  2007;283(5):2488-2494.
Vascular ATP-sensitive K+ channels are inhibited by multiple vasoconstricting hormones via the PKC pathway. However, the molecular substrates for PKC phosphorylation remain unknown. To identify the PKC sites, Kir6.1/SUR2B and Kir6.2/SUR2B were expressed in HEK293 cells. Following channel activation by pinacidil, the catalytic fragment of PKC inhibited the Kir6.1/SUR2B currents but not the Kir6.2/SUR2B. Phorbol 12-myristate 13-acetate (PMA, a PKC activator) had similar effects. Using Kir6.1–Kir6.2 chimeras two critical protein domains for the PKC-dependent channel inhibition were identified. The proximal N-terminus of Kir6.1 was needed, but there was no PKC phosphorylation site in this region. The distal C-terminus of Kir6.1 was crucial where there are several consensus PKC sites. Mutation of Ser354, Ser379, Ser385, Ser391 or Ser397 to non-phosphorylatable alanine reduced PKC inhibition moderately but significantly. Combined mutations of these residues had greater effects. The channel inhibition was almost completely abolished when five of them were jointly mutated. In-vitro phosphorylation assay showed that 4 of the serine residues were necessary for the PKC-dependent 32P incorporation into the distal C-terminal peptides. Thus, a motif containing 4 phosphorylation repeats is identified in the Kir6.1 subunit underlying the PKC-dependent inhibition of the Kir6.1/SUR2B channel. The presence of the phosphorylation motif in the Kir6.1 but not in its close relative Kir6.2 suggests that the vascular KATP channel may have undergone evolutionary optimization allowing it to be regulated by a variety of vasoconstricting hormones and neurotransmitters.
doi:10.1074/jbc.M708769200
PMCID: PMC4132833  PMID: 18048350
13.  A Hybrid Model for Predicting the Prevalence of Schistosomiasis in Humans of Qianjiang City, China 
PLoS ONE  2014;9(8):e104875.
Backgrounds/Objective
Schistosomiasis is still a major public health problem in China, despite the fact that the government has implemented a series of strategies to prevent and control the spread of the parasitic disease. Advanced warning and reliable forecasting can help policymakers to adjust and implement strategies more effectively, which will lead to the control and elimination of schistosomiasis. Our aim is to explore the application of a hybrid forecasting model to track the trends of the prevalence of schistosomiasis in humans, which provides a methodological basis for predicting and detecting schistosomiasis infection in endemic areas.
Methods
A hybrid approach combining the autoregressive integrated moving average (ARIMA) model and the nonlinear autoregressive neural network (NARNN) model to forecast the prevalence of schistosomiasis in the future four years. Forecasting performance was compared between the hybrid ARIMA-NARNN model, and the single ARIMA or the single NARNN model.
Results
The modelling mean square error (MSE), mean absolute error (MAE) and mean absolute percentage error (MAPE) of the ARIMA-NARNN model was 0.1869×10−4, 0.0029, 0.0419 with a corresponding testing error of 0.9375×10−4, 0.0081, 0.9064, respectively. These error values generated with the hybrid model were all lower than those obtained from the single ARIMA or NARNN model. The forecasting values were 0.75%, 0.80%, 0.76% and 0.77% in the future four years, which demonstrated a no-downward trend.
Conclusion
The hybrid model has high quality prediction accuracy in the prevalence of schistosomiasis, which provides a methodological basis for future schistosomiasis monitoring and control strategies in the study area. It is worth attempting to utilize the hybrid detection scheme in other schistosomiasis-endemic areas including other infectious diseases.
doi:10.1371/journal.pone.0104875
PMCID: PMC4131990  PMID: 25119882
14.  Visceral Adiposity Index May Be a Surrogate Marker for the Assessment of the Effects of Obesity on Arterial Stiffness 
PLoS ONE  2014;9(8):e104365.
Objective
The relationship between obesity and cardiovascular disease (CVD) remains unclear. This study aims to describe the relationship between arterial stiffness and obesity in order to investigate the effects of obesity on CVD.
Methods
We collected data from 5,158 individuals over 40 years of age from a cross-sectional study in Nanjing, China. Anthropometric, demographic, hemodynamic measurements and arterial stiffness measured through brachial-ankle pulse wave velocity (baPWV) were obtained. Subjects were grouped by body mass index (BMI), waist circumference (WC) and visceral adiposity index (VAI), a sex-specific index based on BMI, WC, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C).
Results
The multivariate regression analysis revealed a negative but weak effect of BMI (β = −0.047, P<0.001) on baPWV, but failed to demonstrate any significant effect of WC on baPWV while VAI was a positive independent indicator of baPWV (β = 0.023, P = 0.022). The unadjusted baPWV significantly increased across groups with higher obesity categories (P<0.01). Although the positive association was lost after adjustments for confounding factors in the BMI or WC categories (P>0.05), it was still obtained between baPWV and VAI quartile (P<0.01). No differences were observed among the metabolically healthy groups or the metabolically abnormal groups in the BMI and WC categories (P>0.05). However, baPWV significantly increased across groups with higher VAI categories even in the same metabolic category (P<0.01).
Conclusions
This study supports the concept of heterogeneity of metabolic status among individuals within the same obesity range. Obese individuals are at an increased risk of arterial stiffness regardless of their metabolic conditions. VAI may be a surrogate marker for the assessment of obesity and the effects of obesity on arterial stiffness.
doi:10.1371/journal.pone.0104365
PMCID: PMC4126713  PMID: 25105797
15.  HIV/AIDS Patients’ Medical and Psychosocial Needs in the Era of HAART: A Cross-sectional Study among HIV/AIDS Patients Receiving HAART in Yunnan, China 
AIDS care  2012;25(7):915-925.
Background
Since the launch of China’s Free Antiretroviral Therapy (ART) Program in 2002, more than 100,000 HIV/AIDS patients have been treated with highly actively antiretroviral therapy (HAART). However, the current evaluation system for this program mainly focused on its medical outcomes. This study aims to evaluate the medical and psychosocial needs of HIV/AIDS patients after initiating HAART.
Methods
A cross-sectional study was conducted among 499 HIV/AIDS patients who were currently being treated with HAART in three designated hospitals in Luxi City, Yunnan Province. A questionnaire was used to collect information about participants’ demographic characteristics, perceived HIV-related stigma, physician-patient relationship, quality of life, family functioning, etc. Patients’ medical records in the National HIV Information System were linked with their questionnaire by their ART identification number.
Results
Patients on HAART who were infected with HIV through injection drug use and were current smokers typically had poorer physical health than other participants on HAART. Better financial status and better physician-patient relationship were associated with both physical and psychological well-being. Family awareness of the patient’s HIV status was negatively associated with the patient’s psychological well-being. Higher levels of perceived HIV-related stigma were associated with poorer psychological health and poorer family functioning.
Conclusion
This study emphasizes the importance of assuring a caring environment in China’s AIDS treatment program and re-enforces the need to combat the stigma encountered with health providers and the public.
doi:10.1080/09540121.2012.729804
PMCID: PMC3586758  PMID: 23061980
HIV/AIDS; HAART; Patient’s need
16.  The Lack of CuZnSOD Leads to Impaired Neurotransmitter Release, Neuromuscular Junction Destabilization and Reduced Muscle Strength in Mice 
PLoS ONE  2014;9(6):e100834.
Elevated reactive oxygen species (ROS) production and ROS-dependent protein damage is a common observation in the pathogenesis of many muscle wasting disorders, including sarcopenia. However, the contribution of elevated ROS levels to –a breakdown in neuromuscular communication and muscle atrophy remains unknown. In this study, we examined a copper zinc superoxide dismutase [CuZnSOD (Sod1)] knockout mouse (Sod1−/−), a mouse model of elevated oxidative stress that exhibits accelerated loss of muscle mass, which recapitulates many phenotypes of sarcopenia as early as 5 months of age. We found that young adult Sod1−/− mice display a considerable reduction in hind limb skeletal muscle mass and strength when compared to age-matched wild-type mice. These changes are accompanied by gross alterations in neuromuscular junction (NMJ) morphology, including reduced occupancy of the motor endplates by axons, terminal sprouting and axon thinning and irregular swelling. Surprisingly however, the average density of acetylcholine receptors in endplates is preserved. Using in vivo electromyography and ex vivo electrophysiological studies of hind limb muscles in Sod1−/− mice, we found that motor axons innervating the extensor digitorum longus (EDL) and gastrocnemius muscles release fewer synaptic vesicles upon nerve stimulation. Recordings from individually identified EDL NMJs show that reductions in neurotransmitter release are apparent in the Sod1−/− mice even when endplates are close to fully innervated. However, electrophysiological properties, such as input resistance, resting membrane potential and spontaneous neurotransmitter release kinetics (but not frequency) are similar between EDL muscles of Sod1−/− and wild-type mice. Administration of the potassium channel blocker 3,4-diaminopyridine, which broadens the presynaptic action potential, improves both neurotransmitter release and muscle strength. Together, these results suggest that ROS-associated motor nerve terminal dysfunction is a contributor to the observed muscle changes in Sod1−/− mice.
doi:10.1371/journal.pone.0100834
PMCID: PMC4074103  PMID: 24971750
17.  Dynamic assessment of lung injury by ultrasound in a case with H7N9 influenza 
Critical Care  2013;17(3):438.
H7N9 influenza is a new emerging infection and has high mortality. Both chest radiography and computed tomography (CT) had some limitations in assessing such patients. We performed daily lung ultrasound in a patient with H7N9 influenza. Lung ultrasound and lung ultrasound score showed high consistency with CT and the progression of pneumonia. Ultrasound can be adjutant to chest radiography and CT in caring for patients with H7N9 influenza.
doi:10.1186/cc12751
PMCID: PMC3706904  PMID: 23805783
18.  Increased mitochondrial matrix directed superoxide production by fatty acid hydroperoxides in skeletal muscle mitochondria 
Free radical biology & medicine  2010;50(5):592-601.
Previous studies have shown that muscle atrophy is associated with mitochondrial dysfunction and an increased rate of mitochondrial reactive oxygen species production. We recently demonstrated that fatty acid hydroperoxides (FA-OOH) are significantly elevated in mitochondria isolated from atrophied muscles. The purpose of the current study is to determine whether FA-OOH can alter skeletal muscle mitochondrial function. We found that FA-OOH (at low micromolar concentrations) induces mitochondrial dysfunction assessed by decrease in the rate of ATP production, oxygen consumption and activity of respiratory chain complexes I and III. Using methods to distinguish superoxide release towards the matrix and inter-membrane space, we demonstrate that FA-OOH significantly elevates oxidative stress in the mitochondrial matrix (and not the inter-membrane space) with complex I as the major site of superoxide production (most likely from a site upstream of the ubiquinone binding site but downstream from the flavin binding site-the iron sulfur clusters). Our results are the first to indicate that FA-OOH’s are important modulators of mitochondrial function and oxidative stress in skeletal muscle mitochondria and may play an important role in muscle atrophies that are associated with increased generation of FA-OOH’s, e.g., denervation-induced muscle atrophy.
doi:10.1016/j.freeradbiomed.2010.12.014
PMCID: PMC4017321  PMID: 21172427
Oxidative stress; superoxide; fatty acid hydroperoxides; hydrogen peroxide; mitochondria
19.  A Novel Multi-Unit Tablet for Treating Circadian Rhythm Diseases 
AAPS PharmSciTech  2013;14(2):861-869.
This study aimed to develop and evaluate a novel multi-unit tablet that combined a pellet with a sustained-release coating and a tablet with a pulsatile coating for the treatment of circadian rhythm diseases. The model drug, isosorbide-5-mononitrate, was sprayed on microcrystalline cellulose (MCC)-based pellets and coated with Eudragit® NE30D, which served as a sustained-release layer. The coated pellets were compressed with cushion agents (a mixture of MCC PH-200/ MCC KG-802/PC-10 at a ratio of 40:40:20) at a ratio of 4:6 using a single-punch tablet machine. An isolation layer of OpadryII, swellable layer of HPMC E5, and rupturable layer of Surelease® were applied using a conventional pan-coating process. Central-composite design-response surface methodology was used to investigate the influence of these coatings on the square of the difference between release times over a 4 h time period. Drug release studies were carried out on formulated pellets and tablets to investigate the release behaviors, and scanning electron microscopy (SEM) was used to monitor the pellets and tablets and their cross-sectional morphology. The experimental results indicated that this system had a pulsatile dissolution profile that included a lag period of 4 h and a sustained-release time of 4 h. Compared to currently marketed preparations, this tablet may provide better treatment options for circadian rhythm diseases.
doi:10.1208/s12249-013-9975-8
PMCID: PMC3666023  PMID: 23649996
central composite design; circadian rhythm diseases; in vitro dissolution study; multi-unit tablet; sustained-release and pulsatile coating
20.  HDAC 1/4-mediated silencing of microRNA-200b promotes chemoresistance in human lung adenocarcinoma cells 
Oncotarget  2014;5(10):3333-3349.
Chemoresistance is one of the most significant obstacles in lung adenocarcinoma (LAD) treatment, and this process involves genetic and epigenetic dysregulation of chemoresistance-related genes. Previously, we have shown that restoration of microRNA (miR)-200b significantly reverses chemoresistance of human LAD cells by targeting E2F3. However, the molecular mechanisms involved in the silencing of miR-200b are still unclear. Here we showed that histone deacetylase (HDAC) inhibitors could restore the expression of miR-200b and reverse chemoresistant phenotypes of docetaxel-resistant LAD cells. HDAC1/4 repression significantly increased miR-200b expression by upregulating histone-H3 acetylation level at the two miR-200b promoters partially via a Sp1-dependent pathway. Furthermore, silencing of HDAC1/4 suppressed cell proliferation, promoted cell apoptosis, induced G2/M cell cycle arrest and ultimately reversed in vitro and in vivo chemoresistance of docetaxel-resistant LAD cells, at least partially in a miR-200b-dependent manner. HDAC1/4 suppression-induced rescue of miR-200b contributed to downregulation of E2F3, survivin and Aurora-A, and upregulation of cleaved-caspase-3. HDAC1/4 levels in docetaxel-insensitive human LAD tissues, inversely correlated with miR-200b, were upregulated compared with docetaxel-sensitive tissues. Taken together, our findings suggest that the HDAC1/4/Sp1/miR-200b/E2F3 pathway is responsible for chemoresistance of docetaxel-resistant LAD cells.
PMCID: PMC4102813  PMID: 24830600
lung adenocarcinoma; miR-200b; E2F3; histone deacetylase; chemoresistance
21.  Screening and selection of peptides specific for esophageal cancer cells from a phage display peptide library 
Background
Esophageal cancer is a common malignant tumor of the gastrointestinal tract and is typically diagnosed at an advanced stage due to the absence of early clinical symptoms. Although surgery, chemotherapy, and radiotherapy represent the major treatment methods employed for this cancer, the prognosis of esophageal cancer remains poor.
Methods
A Ph.D.-12TM Phage Display Peptide Library was screened using an esophageal cancer cell line, Eca109, and a normal esophageal epithelial cell line to identify novel ligands that selectively bind the surface of esophageal cancer cells with high affinity.
Results
Two polypeptides were isolated that exhibited higher binding affinities and specificity for the Eca109 cells. These peptides were further validated using enzyme-linked immunosorbent assays (ELISAs), immunofluorescence assays, and immunohistochemistry assays.
Conclusion
Two polypeptides with high binding affinities to esophageal cancer cells were isolated from the Ph.D.-12TM Phage Display Peptide Library. Further studies are needed to characterize the biological effects of these polypeptides and to explore the potential for these peptides to be used for the early screening of esophageal cancer or for cell-targeted therapies that would reduce the toxic side effects of cancer treatment.
doi:10.1186/1749-8090-9-76
PMCID: PMC4018990  PMID: 24779651
Phage display; Esophageal cancer cells; Subtractive screening; Targeted cancer therapy
22.  LTP requires a reserve pool of glutamate receptors independent of subunit type 
Nature  2012;493(7433):495-500.
Summary
Long-term potentiation (LTP) of synaptic transmission is thought to be a key cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic tail of the AMPA receptor subunit GluA1. To find the minimum necessary requirement of the GluA1 C-tail for LTP in CA1 hippocampal pyramidal neurons, we used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors with transfected subunits. In striking contrast to the prevailing model, we found no requirement of the GluA1 C-tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with dramatically decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. These results demonstrate the synapse’s remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in our thinking with regard to the core molecular events underlying synaptic plasticity.
doi:10.1038/nature11775
PMCID: PMC3998843  PMID: 23235828
23.  Parkinson’s Disease and Risk of Fracture: A Meta-Analysis of Prospective Cohort Studies 
PLoS ONE  2014;9(4):e94379.
Backgrounds/Objective
Parkinson’s disease (PD) is the second most common neurodegenerative disease among the elderly population. However, epidemiological evidence on the relationship of PD with risk of fracture has not been systematically assessed. Therefore, we performed this meta-analysis of prospective studies to explore the association between PD and risk of fracture.
Methods
PubMed, Embase, Web of Science and Cochrane Library up to February 26, 2014 were searched to identify eligible studies. Random-effects model was used to pool the results.
Results
Six studies that totally involved 69,387 participants were included for analysis. Overall, PD patients had an increased risk of fracture compared with control subjects (pooled hazard ratio = 2.66, 95% confidence interval: 2.10–3.36). No publication bias was observed across studies and the subgroup as well as sensitivity analysis suggested that the general results were robust.
Conclusion
The present study suggested that PD is associated with an increased risk of fracture. However, given the limited number and moderate quality of included studies, well-designed prospective cohort studies are required to confirm the findings from this meta-analysis.
doi:10.1371/journal.pone.0094379
PMCID: PMC3979831  PMID: 24714656
24.  Effects of silencing RIP1 with siRNA on the biological behavior of the LoVo human colon cancer cell line 
Oncology Letters  2014;7(6):2065-2072.
The present study aimed to investigate the effects of silencing RIP1 by small interfering RNA (siRNA) on the biological behavior of the LoVo human colorectal carcinoma cell line and to provide evidence for the feasibility of colorectal cancer gene therapy. LoVo cells were divided into the RIP1 siRNA group, the blank control group and the negative control group. Chemically synthesized siRNA targeting RIP1 (RIP1 siRNA) was transfected into LoVo cells. Following transfection of the RIP1-targeted siRNA into the LoVo cells, the expression of the RIP1 gene was effectively inhibited. The results demonstrated that RIP1 effectively regulated the malignant biological behavior of the LoVo colon cancer cell line. Furthermore, the proliferation, motility and invasiveness of LoVo cells were inhibited by siRNA knockdown of RIP1. The results revealed that the RIP1 gene has an important role in the regulation of proliferation and apoptosis in colorectal carcinoma cells.
doi:10.3892/ol.2014.2040
PMCID: PMC4049674  PMID: 24932290
RNA interference; RIP1 gene; colorectal carcinoma
25.  Engagement of immune effector cells by trastuzumab induces HER2/ERBB2 downregulation in cancer cells through STAT1 activation 
Introduction
Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer for more than a decade. However, reports on the involvement of HER2 downregulation in trastuzumab’s mechanism of action are inconsistent. The aim of this study is to investigate if the dependence of trastuzumab-mediated cancer cell HER2 downregulation on immune effector cells represents a novel mechanism of action for trastuzumab.
Methods
HER2 expression was evaluated by Western blotting, flow cytometry, and real-time polymerase chain reaction (PCR) in cell lysates from co-cultures of multiple cancer cell lines with peripheral blood mononuclear cells (PBMCs) in the presence or absence of trastuzumab. The engagement of immune cells by trastuzumab through Fc gamma receptors (FcγRs) was tested using three trastuzumab variants with compromised or no Fc (fragment crystallizable) functions and FcγRs blocking experiments. The engagement of immune cells by trastuzumab in HER2 downregulation was also evaluated in in vivo mouse xenograft tumor models.
Results
HER2 downregulation of cancer cells by trastuzumab occurred only when trastuzumab was actively engaged with immune cells and cancer cells, as demonstrated consistently in co-cultures of cancer cell lines with PBMCs and in vivo mouse xenograft tumor models. We further demonstrated that HER2 downregulation in cancer cells by immune-cell-engaged trastuzumab was at the transcriptional level, not through the HER2 degradation pathway. Activation of signal transducer and activator of transcription 1 (STAT1) in cancer cells by the increased interferon gamma (IFN-γ) production in immune cells played an important role in downregulating HER2 in cancer cells upon engagement of immune cells by trastuzumab. Furthermore, HER2 downregulation in cancer cells induced by trastuzumab engagement of immune cells was correlated with the antibody’s antitumor efficacy in vivo.
Conclusions
This study reveals that engagement of immune effector cells by trastuzumab induces HER2 downregulation in HER2-expressing cancer cells, which represents a new function of immune cells in trastuzumab-mediated antitumor efficacy and serves as a novel mechanism of action for trastuzumab. Our results imply that HER2 downregulation in cancer cells treated by trastuzumab may predict active engagement of immune effector cells in tumor microenvironment.
doi:10.1186/bcr3637
PMCID: PMC4053225  PMID: 24693969

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